As I waited to speak with Dr Siddhartha Mukherjee on a cold December morning in New York City, I found myself staring at the last of the leaves that pressed into my window from a Callery Pear tree below. In summer, its branches had offered its foliage as a canopy for all those who walked beneath it. But it was winter now. A whole life cycle – from tendrils to senescence – had gone by and it was only at this late hour that I had begun to notice them carefully.
Outside, the sun continued to lend its faint golden-yellow to those branches, all of which were now emptied of leaves. It was a relentless cycle of life and death – one that has played out for millions of years and will continue to do so long after we are all gone. Driving this unceasing set of actions and transformations were cells – those billions and trillions of microscopic entities that come together to form living beings, their organs and body parts, and in the case of humans – you and me.
Perhaps my reaction was inevitable – “cells” were on my mind as I had been thinking about Mukherjee’s latest book, The Song of the Cell. It follows his extraordinary debut – a biography of cancer titled The Emperor of All Maladies, and a fascinating second book, The Gene. This third book, while being about cells, also straddles the worlds of cellular therapy, the history of medicine, the politics of science, and more.
Born in India and educated at the universities of Stanford, Oxford, and Harvard, Mukherjee is a cancer physician and researcher, a professor of medicine, a Pulitzer Prize winner, and a writer of reflective and scrupulously researched books on medicine and, arguably, the human condition itself. His world has a ring of permanence and heaviness to it. He spends his days among the sick and those suffering from random mutations – each of whom is looking for a life of normalcy, even if the word “normal” is complex.
This world of disease and cure, suffering and alleviation, is both intimate and yet forbiddingly alien. Viewed thus, Mukherjee’s books are like lighthouses that scan and shine light upon sections of the great unknown, as a result of which the reader forms some notions about the contours of what lies out there.
When we spoke that morning, he had recently returned to New York and had woken up very early to talk to his medical team in India. His voice was measured, perhaps a bit tired, but there was no impatience in it. That exhaustion had steadily caught up to him was not surprising because he had been travelling extensively the past few weeks – California, New York, London – as he spoke to a diverse group of audiences, all of whom must have gathered to hear him describe the farthest horizons of modern biological sciences.
Despite so much else going on, Mukherjee had generously agreed to speak to me. Somewhere at the back of my head was the constant sense that I was infringing on his time which, at the very least, he could have used elsewhere for more productive or personal purposes, including with his family—his two daughters and his wife Sarah Sze, who is an artist of much renown. Excerpts from the conversation:
Let us start at the end of your book where you talk about the title of your latest book, The Song of the Cell – what does the word “song” mean here?
There are really two reasons that this book is called The Song of the Cell. And I should tell you that I came up with the title very late in the book. This book had a different title initially. The first song is an internal song. And that refers to the idea that comes very early in the book, which is that if you think about genes, which has captured human imagination as sort of symbols of life.
The irony is that genes themselves are lifeless. DNA is a molecule. DNA, which encodes genes, is a molecule. And that molecule is lifeless. It’s a chemical, and it’s only the cell that enlivens that molecule. So in some ways there’s a comparison between DNA being a score, a musical score and the cell playing out its music. And that’s the internal song of the cell that comes very early in the book.
But there’s a second song that cells play. That comes much later in the book, which is much less known. And that’s the song that cells play when they communicate with one another when there is a system of cells. And I think that is an external song. A song between cells. A song of the cellular civilisation that we live in, as we’re made of trillions of cells. And they are communicating with each other in ways that we don’t know yet. They are creating ecologies. They’re creating interactions and communications that we don’t yet know. And that’s the second song: that’s the unknown song. And that comes very late in the book because of course, that’s much less discovered. So these two ideas basically form the title of the book The Song of the Cell.
If a common reader without any medical training were to ask you what is your book about, how would you describe it? Is it a history of ideas which have led us to the present? Or is it like a map from the 16th century about what humanity has discovered and what we don’t know about the great unknown out there. And about how some of what we think we know today could be wrong, say 30 years from now.
You’ve read my other books, so you know I don’t write in a genre. I write outside genres. Or I don’t believe in a sort of genre writing. So this book if you twist it one way – sort of like a kaleidoscope, it reads in one manner. If you twist it another way, it reads in a different way.
In some ways, it’s a medical history. There is personal history and memoir in it. There’s the history of my becoming a physician. There are case histories which sort of mimic or resemble Victorian case histories. There is a lot of, you know, deep science. That goes into the book, some of which is very new. Some may or may not survive our explorations in time. So it’s a mix of all of these and different readers come to the book in different ways, and they come to the book in ways that are unique to what they’re looking for.
This is a book as much for cell biologists as it is for someone who’s just interested in learning about the world. It brings you into, I think, a new world, which is the world of cells. And there’s a very specific reason for that. And that is because if you think about biology – biology is based on three grand unifying theories.
One, of course, is the Theory of Evolution. The second is the universality of genetics and the genetic code. And the third is cell theory. The fact that all living organisms are made of cells. Now there are a thousand books about evolution and thousand books of our genetics – I’ve written one of them myself – but cell theory got [little] in this. And, even though arguably from the standpoint of medicine, it’s probably the most important of all of these theories. If you want to call this book an intellectual history of the cell, [the fact is] there are very few intellectual histories of the cell. And that’s why this book; and the scope of the book is so large because of that reason.
There is a wonderful line in the book which moved me greatly – about returning home after long alien days in a foreign university. What awaits you at home is a father’s love that is both quiet and deep, a mother’s abiding presence. You write about arriving in India on that occasion: “The man at Customs [in Delhi] asked me for a small bribe, and I felt like hugging him; I was home.” When I read that it made me laugh. You obviously know India in a very intimate kind of way. In the last three decades, you must have seen India evolve in good and bad ways. What does India mean to you today as somebody who lives here and travels the world over? Or do those boundaries not really matter because you’re living and thinking about something so universal as the human body?
I think to a large extent those boundaries [of nation-states] don’t matter to me. I’ve always lived multiple lives and allowed myself to travel in space and time in my mind, in different ways in different places. So I think that [national boundaries] itself doesn’t matter to me. That is not really of consequence. I think there’s particular challenges in terms of medicine in India that I feel acutely.
As you know, I’ve launched clinical trials in India which are still very active. Part of the reason I have to wake up really early is that I still am very deeply involved in those trials. It’s not like I’ve run those trials and set them free. I collaborate with an incredible team of physicians and scientists. And I can tell you that the quality of care and discussion and thinking that goes into this very radical clinical trial that we’re doing in India, could be anywhere in some ways. It could be I could be speaking with my colleagues at Columbia [University], or I could be speaking with my colleagues anywhere in the world. And in fact it is a collaboration between India and Spain which itself is interesting.
So, in some ways, I feel totally at home – in both contexts. But in other ways I feel there’s some very foreign elements that I can’t quite fathom and I’m not sure what it would take to fathom them. The trial is being run out of Bangalore. It takes me three hours to travel from Delhi to Bangalore, give or take, and then it takes me another three hours to go from Bangalore to the hospital – from the airport to the hospital.
And when I reach the hospital, having passed by roads piled up with garbage, I all of a sudden encounter a place that is – because we are harvesting and culturing T-cells – one of the cleanest environments conceivable on the planet. There’s not one single pathogen that’s allowed to enter.
You have to wear a [sort of] hazmat suit – not a real one, but you have to gown and suit and glove yourself. Every surface is sterilised and polished to look like a mirror. And the contrast [between the road to the hospital and the hospital itself] is just shocking to me. I’ve learned to deal with it over time. I don’t feel any difference in a fundamental way between one place and the other as far as the science, the technology, the clinical care is concerned.
If you were to write a sort of a history of modern India through human bodies – as you know, Indians were shorter, weighed less in 1947 compared to today. We have new types of diseases – you write about the emergence of heart disease in America in the 1930s, the rise of a sedentary lifestyle, and so on. Is it possible to write such a book which tracks the history of the Indian Republic on one side and a history of Indian bodies on the other? And marry the two into one narrative.
Yes, I think it would be a very interesting history. I’m not sure I’m the right person to write it, but I think it would be a very interesting history. I mean, I think this is true for the world in general. This is not specific to India, but across the world – hypertension is now a major cause of death in Tanzania, which we think of as a country where you would imagine that infectious diseases would be so predominant that they would really wipe out all other causes of death.
Everywhere in the world, epidemiology and the face of epidemiology are changing. And so again, I don’t think I would make a distinction between India and other parts of the world. I think you can write such a book. I think it would be interesting to write such a book more globally. Given body and changes in the human body over time. And what does that mean for medicine? What that means for epidemiology, etc.
And I think it has very much to do with very broad global shifts. In nourishments. In what food we eat, how we eat the food, how we process the food, what chronic diseases we’re exposed to, the changes in our lifestyles, the changes in how much food we are given and how we store that food, how our metabolism has changed. That I would imagine that if I were to do – a corner of my life that works on metabolism, how metabolism has changed between the centuries – I suspect that that book would be better written not just from an Indian perspective, but from a global perspective.
In everyday life, when we think of depression, it is the heart as an organ that we assume, metaphorically, is afflicted. (“Depression is a flaw in love,” as Andrew Solomon writes.) But you remind us, from your own experience, that depression is also a cellular problem. A problem of how neurons respond to neurotransmitters. Can common people without a medical education think about depression in new ways, in similar ways to how we think about heart attacks or kidney stones – without social stigma, without a need to hide it? I remember reading your piece on depression in The Guardian. I keep thinking about the great amount of effort that goes into hiding mental illnesses, including in my own family.
The general view of any mental illness is very flawed in our society. There’s a lot of blame; there’s a lot of, I would say, unsolicited misunderstanding of mental illness. I mean, one of the reasons to publish that [Guardian] piece was to remind people that depression is in some ways just as much an organic illness as any other disease. Hypertension, coronary arteries disease. It’s an alteration in cells. In this case, they happen to be cells that regulate mood and regulate mood circuits.
And we think of mood and mood circuits as, appropriately, as a combination of environmental and genetic influences as well as, of course, ultimately, cell biological instances. One thing I wanted to stress in that [Guardian] piece is that no one denies that there’s a psychosocial, environmental, situational component to depression. That’s not what is at stake here.
But what’s important is that if you think about cell biology and the cell biology expression, you realise that ultimately all diseases have to move through their impact on cells. In other words, the psychosocial, the environmental, the many fold influences that modify depression are nonetheless influences that modifies cellular behaviour. And I think it’s very important to realise that ultimately there is an influence on cellular behaviour. And the more quickly we realise this, the better it is in terms of our understanding and potentially our capacity to heal depression.
One of the profound questions you ask in your book is “Why did we ever leave the single-celled world? Why did ‘we’ become ‘we’ – that is, multicellular organisms?” Like many children, what I had learnt was that there were unicellular organisms and then through some incredible “leap” across a valley of contingencies, “multicellular” life began. You write that, in contrast to what we have been taught, this transition is a “minor major transition”. What does this phrase mean? And how does this affect our understanding of cells?
Just to start off with single-celled organisms, like bacteria, they are phenomenally successful. They can live in boiling water and sulphurous vents in volcanoes and wherever we find them – inside the body, outside the body. So for a long time people studying evolution and evolution and evolutionary biology imagined that the evolution of multicellular organisms would represent an enormous leap in evolutionary history.
But what’s interesting was that it turned out that... that’s not the case. That, in fact, there’s a very strong evolutionary drive that we don’t understand. But there is nonetheless a very strong evolutionary drive towards becoming multicellular. And if you look at the history of evolution using powerful genetic and evolutionary tools, you find that this leap has been made not just once, but independently, multiple times. Again suggesting that the drive [towards multicellularity] was very strong, such that independently you obtained multicellular organisms. So that’s just another way of saying that the transition from single cell organisms into multicellular organisms was a transition that was not something bizarre and unusual – but something that actually happened in evolution multiple times.
Your books, all three of them, are filled with stories of scientists and medical professionals over the centuries and in the recent past. In some sense, it is like a history of modern medicine. Most of us think about human bodies in the here-and-now; but you shed light on how our thinking about bodies has evolved. New theories, conjectures, disputations, wrong conclusions, and even the hegemony of pet theories till they are washed away by evidence. You show that knowledge has a politics of its own. But when I talk to my friends in medicine, they are often completely divorced from a historical consciousness. They are so overwhelmed by stuff they have to study on a daily basis that the history largely falls out of their curriculum, or at least in their immediate mind. From a pedagogic and practical point of view – what do you think about this?
It’s a big problem from a pedagogy point of view because when you learn to do any form of science, including medical science, it’s very important to understand and to appreciate where the science is coming from, and where it’s going. What its history is, what its history was. How its history changed. Because it informs us with a much broader understanding of why people did the things they did. In fact, in a prior book, I had said, ‘History reverberates.’
It comes back in ways that are unexpected. And there’s a lot to learn from it. The mistakes, the misconceptions that we make today in medicine may be completely different on a superficial level. But at a deeper conceptual level, they’re actually very similar. They may be mistakes in a fundamental conception. They may be paradoxes. And the way people went around solving these paradoxes using combinations of natural physiology, cellular physiology, chemistry, biochemistry are actually just as relevant today as they were years and years ago.
Many of my own, much of my own sort of musings and thinkings and in fact, experimental work in medicine has been inspired by questions like this. Questions like “why something is not the case”. And those questions – if you look through history, especially the history of medical pedagogy, or if you look through the history of medicine, you’ll find those questions buried inside there.
It’s not the first time we’ve asked some very fundamental questions. Like, what is aging? And why does aging move, move in the following manner. I mean, remember if you take a subject that I think is more dear to your own heart, remember that modern physics was really born in some ways out of Einstein asking a question about what it would be like to ride a beam of light. That question is not a contemporary question. There’s nothing in that question that has to do with today. That question could have been asked in 1920, it could have been asked in 1820 or in 1520. The answers to the questions changed because our tools changed. But the fundamental idea that the great questions remain great questions even today, I think, is something that you can only learn from history.
When I was reading the sections on Thalidomide and birth defects – your book offers a stunning glimpse into how at a cellular level great harm can be done by chemicals – I kept thinking of the incredible photos by Madhuraj, a great photojournalist who works for Mathrubhumi, who documented the deformities in children who had been exposed in utero to a chemical called Endosulfan. You write, “If this book is about the birth of cellular medicine, it must also mark the birth of its demonic opposite: the cellular poison.” As India modernises rapidly, as chemicals, plastics, and other pharmacological products actively or unwittingly enter our bodies – can people be educated about it all? Do you think that kind of a discussion is itself possible in a very large democracy with all kinds of problems of communication and cleavages?
I think it’s very possible. And I think that’s what people are looking for, people are looking for a deeper understanding of what life is like at the cellular level and what pathology is like at the cellular level. Because otherwise there’s no understanding. You don’t understand why things are happening.
Thalidomide is itself very interesting. We understood the negative effects of thalidomide long, long before the mechanism by which thalidomide works was discovered. That wasn’t discovered until the 2010s, 2015s even. That is several decades after the thalidomide controversy. I shouldn’t say controversy but the Thalidomide devastation. So I think that pointing out what the problem is is the first step. How that translates into changes in cellular physiology is a completely separate question and a separate step. And that separate step really relies on understanding how cells work and how they fail to work in cases like Thalidomide.
One of the clarifying moments for me was early on in the book when you describe how you think when you face an undiagnosable disease. You write that you have a three part rule: “germs, cells, risk”. You ask: Is there an outside agent involved (bacteria or virus), is the cellular pathology under stress, and is the disease a consequence of exposure to some pathogen, a family history, or an environmental toxin? I thought about this rule especially in the context of Kerala, where we have a fairly alarming rise in cancer across the state. There is hardly any family that doesn’t have somebody who hasn’t been affected by it. Do you have an intuition of what kind of physical changes may have led to this kind of seeming explosion? Or is it just improved diagnosis and reporting and so on?
I think it’s multifactorial. I think there is certainly improved diagnosis and reporting. But I also do think that a major factor that’s driving cancer in the world is really the aging of the population. I think that in the first book, in Emperor of All Maladies, I state that cancer arises in the double negative when the other killers are killed.
So, when tuberculosis deaths are decreased, when other diseases that would normally kill us are decreased, that’s when cancer begins to rear its head. It’s a disease of old age. So I think there’s more reporting. There’s more early diagnosis. There are, of course, new carcinogens that have been introduced into the world. You mentioned some of them. One major factor is obesity and metabolism. So our metabolism has changed and people are more obese. We know that that’s a known risk factor for cancer. In the 1920s and 1930s we saw an explosion in cigarette smoking – also a major risk factor for cancer. So. I think it’s multifactorial: more reporting, newer carcinogens including, as I said, smoking and obesity, and, finally, the aging of the population.
In the middle of the book is a section on cellular technology used for sex-determination, IVF and gene-editing. You write extensively about the Chinese geneticist He Jiankui, who inserted edited gene-lines (without any scrutiny from peers) to make embryos and inserted them into a womb. He was subsequently arrested and was released recently. But then you write about the Russian geneticist Denis Rebrikov, who is embarking on similar interventions. One gets the feeling from such examples that we may be able to stop a few cases, but the lure of gene-editing one’s to-be-born children for understandable reasons (such as to prevent breast cancer) is quite widespread and understandable. Even if the risks of doing this are relatively unknown, it seems the genie is out of the bottle and more such experiments will only continue. How should we collectively think about this?
I think these experiments have very broad consequences for humans. And I really think that these experiments should be halted until we figure out what’s permissible and what’s not permissible. I don’t think we should just sort of free ride our way into them and then in retrospect figure out how and when and what the barriers and limits are.
If you look at the history of genetic engineering again, you look at my second book, The Gene, there’s a long discussion of the Asilomar Conference [Asilomar II, California, 1975], where of course, very fundamental things about what was permissible and not permissible in terms of intervening on recombinant DNA was first established. But importantly, that was established prospectively, not retrospectively. It’s not like we went back and started working on recombinant DNA and figured out later how to manage it and solve that problem.
So by analogy, I think it’s very important to work on this now. And to figure out how to do it in a way that’s palatable and really conforms to our understanding of human norms and human behaviour. And I strongly think that it should be done in advance – we shouldn’t stumble our way through this. We should do it in a systematic manner. And in a manner that takes inputs from bioethicists and ethicists in general. But also from the broad public, from you and me, because we are invading on something whose stewardship – I’m talking about the human genome – whose stewardship very much has to do with the stewardship of ourselves, in general. And I think that taking it casually is to make a terrible mistake.
The second part of this interview will appear on Saturday, January 7, 2023.
Keerthik Sasidharan is the author of The Dharma Forest (Volume 1 of The Dharma Cycle), which was long listed for the JCB Prize for Literature. Volume 2 will appear in late 2023. He can be found here on Twitter.